This grant application seeks to uncover the molecular and neural networks underlying social attachment behaviors in prairie voles. Humans form attachments at many levels of social interactions, including with spouses, family members, friends, and other members of the community. The neurobiological mechanisms that control the formation and maintenance of social attachment remain poorly understood. This is in part because traditional genetic model systems such as mice, fish, flies, and worms do not exhibit social attachment behavior as adults, precluding the use of powerful molecular genetic approaches to dissect mechanisms underlying social attachment behavior. Prairie voles are small rodents that form an enduring social bond between adults, and they also display other related afflictive behaviors. Pharmacologic studies in prairie voles have implicated vasopressin and oxytocin signaling in the control of social attachment behaviors. However, there are significant limitations of these pharmacological manipulations such that the genetic requirement of specific neuropeptide signaling pathways remains unclear. Progress in uncovering the molecular and neural circuit basis of social attachments in prairie voles has been slowed by the absence of gene targeting techniques as well as by the absence of identification of behaviorally-salient neurons. In this grant application, we propose to develop gene targeting technology in prairie voles, focusing on vasopressin and oxytocin signaling pathways (Aim 1). In Aim 2, we propose to analyze behavioral deficits in social attachment in prairie voles genetically mutant for these signaling pathways. Finally, in Aim 3 we propose developing molecular tools to uncover genetic and neural pathways underlying social attachment in prairie voles. Taken together, our studies will enable gene targeting in prairie voles and elucidate neural mechanisms that control social attachment behavior. Health relatedness: Social attachments are thought to be critical for our mental health and for success in personal and professional interactions. Failure to form or maintain social attachments is often an early indicator of a serious mental illness such as autism spectrum disorder or schizophrenia. Strikingly, vasopressin and oxytocin are also thought to play a critical role in human social attachments, and dysregulated signaling via these neuropeptide pathways has been implicated in autism spectrum disorders. Our proposal seeks to establish the prairie vole as a new mammalian genetic model system and to uncover mechanisms underlying social attachment behavior. These advances may therefore provide a useful model system to study social behaviors relevant to human health and mental illnesses.